The present invention relates to the use of functionalized (per) fluoropolyethers as preservatives of compositions for topical use, specifically cosmetic compositions.
The maintenance in the time of the homogeneity, of the appearance and of the organoleptic properties of cosmetic formulations, as well as of the dermatological and pharmaceutical ones, is an essential requirement for the marketing of these compounds. For these reasons the use of preservatives is in many cases indispensable.
Preservatives are regulated through proper lists with indications of no use and of the allowed maximum doses. The preservative often has a local irritating and allergenic potential activity and therefore the use is limited to the minimum doses necessary to assure the compound protection from the biological contamination for the validity time of the formulation. The compositions containing water are those sensitive to the bacteria, moulds and yeasts contamination, in a proportional way to the water content. Said compositions are for example gels and emulsions and among the latter in particular oil-in-water emulsions.
The preservative must be a subsantially water-soluble compound at the concentrations at which it is used, and it must be active on a wide spectrum of microorganisms (gram-positive bacteria, gram-negative bacteria, yeasts and moulds). In general a preservative is effective only towards some kinds of microorganisms but not towards all. Therefore the activity spectrum towards the various kinds of microrganisms is enlarged by using mixtures of preservatives. Alternatively only one preservative could be used, but in this case its concentration should be increased so that the compound is B effective towards a wider spectrum of microorganisms. The drawback is that these high concentrations are generally not allowed from the rules of the various countries.
It is known that it is possible to reduce the preservative amount by adding to the formulation a surfactant amount of about 5-10% by weight. The use of surfactants has however the drawback to substantially modify the formulation and the application properties since surfactants are aggressive substances. It is well known that in cosmetic compositions the surfactants confer detergent properties wherefor for example the protective creams become detergent creams, and therefore rinsing products.
It is possible to avoid the addition of preservatives by using formulations containing high concentrations of some excipients, for example water-soluble substances, such as for example polyols, sugars, salts, etc. In these cases a partial protection is obtained, for example from bacteria but not from fungi (yeasts and moulds).
Alcohols and glycols, at high concentrations, higher than 15% by weight, can also be used. Ethanol is for example used at concentrations higher than 20% by weight. The production cost of these formulations is often high and contra-indications as for the local skin tolerability is concerned can occur.
In the prior art it is therefore known how to reduce or eliminate preservatives from the formulations of the products for topical use, in connection with their undesired local irritating or allergenic properties, by using to excipients which however have the drawback, as said, to be less effective than preservatives and to impose some restrictions as regards the formulation, or to cause in their turn skin tolerability problems.
The need was felt to formulate compositions for topical use without preservatives, in order to avoid undesired side effects at local skin level, maintaining the protection from contamination both of gram-positive and gram-negative bacteria and of yeasts and moulds, which typically requires the use of preservatives.
The Applicant has surpirisngly and unexpectedly found that it is possible to solve this technical problem by adding to said formulations for topical use containing water a well defined compound as indicated hereunder.
An object of the present invention is the use as preservative, in formulations for topical use containing water, of a component A): (per)fluoropolyether phosphate of general formula:
Rfxe2x80x94[CF2CH2xe2x80x94Oxe2x80x94Lxe2x80x94P(O) (OZ1) (OZ2)]lxe2x80x83xe2x80x83(I) 
wherein l=1 o 2;
L is a bivalent linking group, preferably of the type (CHR1CHR2O)n wherein R1, R2 equal to or different from each other are selected from H, CH3; n is an integer in the range 1-50, preferably 1-6;
Z1 equal to or different from Z2 selected from H, alkaline or ammonium cation, di- or tri-alkanolammonium cation wherein alkanol comprises from 1 to 20 C atoms, preferably 1-4 C atoms, di- or tri- or tetra-alkylammonium cation wherein alkyl comprises from 1 to 20 C atoms, preferably 1-4 C atoms, or Rfxe2x80x94CF2CH2xe2x80x94Oxe2x80x94Lxe2x80x94;
Rf represents a (per)fluoropolyether chain having number average molecular weight in the range from about 400 to about 1,800, preferably from 500 to 1,300, said (per)fluoropolyether chain comprising repeating units selected from one or more of the following:
a)xe2x80x94(C3F6O)xe2x80x94;
b)xe2x80x94(CF2CF2O)xe2x80x94;
c)xe2x80x94(CFL0O)xe2x80x94, wherein L0=xe2x80x94F, xe2x80x94CF3;
d)xe2x80x94CF2(CF2)z,CF2Oxe2x80x94, wherein zxe2x80x2 is an integer 1 or 2;
e)xe2x80x94CH2CF2CF2Oxe2x80x94.
The preferred formulations comprise also:
component B): a solvent selected from linear or branched when possible alcohols, from 2 to 3 carbon atoms and ethers thereof, preferably methyl; linear or branched glycols from 2 to 6 carbon atoms or linear or branched mono alkyletherified glycols wherein the alkyl group ranges from 1 to 4 carbon atoms; dimethoxymethane, acetone.
When Rf is monofunctional (l=1), an end group is of the perfluoroalkyl type such as for example CF3O, C2F5O, C3F7O; optionally in perfluoroalkyl end groups one fluorine atom can be replaced by one chlorine or hydrogen atom; examples of these end groups are Cl (C3F6O), H (C3F6O).
The preferred compound of general formula (I) is the one in which Z1 and Z2 are different from Rfxe2x80x94CF2CH2xe2x80x94Oxe2x80x94Lxe2x80x94; preferably Z1xe2x95x90Z2xe2x95x90H and in the formula (I) l=2.
In particular Rf is of the bifunctional (per) fluoropolyether type and it has preferably one of the following structures:
1)xe2x80x94(CF2O)axe2x80x94(CF2CF2O)bxe2x80x94
with b/a comprised between 0.3 and 10, extremes included, a being an integer different from 0;
2)xe2x80x94(CF2xe2x80x94(CF2)zxe2x80x2xe2x80x94CF2O)bxe2x80x2xe2x80x94
wherein zxe2x80x2 is an integer equal to 1 or 2;
3)xe2x80x94(C3F6O)rxe2x80x94(C2F4O)bxe2x80x94(CFL0O)txe2x80x94,
with r/b =0.5-2.0 (r+b)/t =10-30, b and t being integers different from 0;
4)xe2x80x94(OC3F6)rxe2x80x94(CFL0O)txe2x80x94OCF2xe2x80x94Rxe2x80x2fxe2x80x94CF2Oxe2x80x94(C3F6O)rxe2x80x94(CFLO0O)txe2x80x94
5)xe2x80x94(CF2CF2CH2O)qxe2x80x2xe2x80x94Rxe2x80x2fxe2x80x94Oxe2x80x94(CH2CF2CF2O)qxe2x80x2xe2x80x94
wherein:
Rxe2x80x2f is a fluoroalkylene group from 1 to 4 carbon atoms;
L0 is selected between F, CF3;
6)xe2x80x94(C3F6O)rxe2x80x94OCF2xe2x80x94Rxe2x80x2fxe2x80x94CF2Oxe2x80x94(C3F6O)rxe2x80x94
wherein in said formulas:
xe2x80x94(C3F6O)xe2x80x94 can represent units of formula:
xe2x80x94(CF(CF3) CF2O)xe2x80x94 and/or xe2x80x94(CF2xe2x80x94CF (CF3)O)xe2x80x94
a, b, bxe2x80x2,qxe2x80x2, r, t, are integers, the sum of which is such that Rf shows values of number average molecular weight {overscore (M)}n in the range from about 400 to about 1,800, preferably 500 to 1,500.
The preferred (per)fluoropolyether chain Rf is selected from the following structures:
from the bifunctional ones (1=2):
xe2x80x94(CF2O)axe2x80x94(CF2CF2O)bxe2x80x94;
xe2x80x94(C3F6O)rxe2x80x94(C2F4O)bxe2x80x94(CFL0Otxe2x80x94;
from the monofunctional ones (l=1):
xe2x80x94(C3F6O)rxe2x80x94(CFL0O)txe2x80x94;
wherein L0 and the a,b,r,t indexes have the above indicated value, still more preferably xe2x80x94(CF2O)axe2x80x94(CF2CF2O)bxe2x80x94, wherein the a and b indexes have the above indicated values.
The compounds of formula (I) preferably used according to the present invention are those wherein L=(CH2-CH2O)n n being an integer from 1 to 3; Z1 equal to or different from Z2 is selected from H, NH4, or an alkaline metal cation; l=2.
The compounds, according to the general formula (I), having the following formulas, are still more preferred:
CF3xe2x80x94O(CF2CF(CF3)O)r(CF2O)axe2x80x94CF2xe2x80x94CH2 (OCH2CH2)nOxe2x80x94PO(OH)2xe2x80x83xe2x80x83(II) 
wherein r/a=0.5-2.0 and n=1-2;
xe2x80x94CF2xe2x80x94(CF2CF2O)b(CF2O)4xe2x80x94CF2xe2x80x94[CH2xe2x80x94(OCH2CH2)nOxe2x80x94PO(OH)2]2xe2x80x83xe2x80x83(III) 
wherein b/a=0.5-3.0 and n=1-2;
wherein a, b and r have the above mentioned meaning.
The (per)fluoropolyethers of general formula (I) are obtainable by the well known processes in the prior art, see for example the patents, herein incorporated by reference, U.S. Pat. Nos. 3,665,041, 2,242,218, 3,715,378, and EP 239,123. The functionalized fluoropolyethers having a hydroxyl termination are obtained for example according to EP 148,482, U.S. Pat. No. 3,810,874.
The preparation of the monofunctional (per)fluoropolyether phosphates of general formula (I) wherein Rf has a pefluoroalkyl end group can be carried out by reacting the corresponding monohydroxy-ended (per)fluoroalkylenoxides with POCl3. A molar ratio POCl3/hydroxy-ended compound in the range 2/1-10/1, preferably 6/1-8/1 is used. The reaction is carried out by slowly dropping the monohydroxy-ended (per)fluoropolyether in POCl3, at a temperature in the range 50xc2x0-100xc2x0 C., preferably 70xc2x0-80xc2x0 C., eliminating the HCl vapours by a KOH trap. The POCl3 excess is removed by distillation while the formed adduct is hydrolyzed by H2O. The hydrolyzed adduct is furtherly reacted for example with an equimolar amount of hydroxy-ended (per)fluoropolyether compound to form the monoester.
The separation of the obtained product is carried out by extraction with a suitable organic solvent, such as for example ethyl acetate. The product of formula (I) is separated from the organic phase according to known techniques, for example by evaporation of the solvent.
The preparation of the bifunctional (per)fluoropolyether phosphates (in this case Rf of formula (I) has not a pefluoroalkyl end group) can be carried out by reacting the corresponding di-hydroxy-ended (per)fluoroalkylenoxides with POCl3. A molar ratio POCl3/hydroxy-ended compound in the range 4/1-20/1, preferably 12/1-16/1 is used. The reaction is carried out by slowly dropping the hydroxy-ended compound in POCl3, at a temperature in the range 50xc2x0-100xc2x0 C., preferably 70-80xc2x0 C., eliminating the HCl vapours by a KOH trap. The POCl3 excess is removed by distillation while the formed adduct is hydrolyzed by H2O. The separation of the product is carried out by extraction with an organic solvent, such as for example ethyl acetate. The product is separated from the organic phase according to known techniques, for example by evaporation of the solvent.
The (per)fluoropolyether phosphate is carried into the compositions for topical use starting from concentrated compositions comprising, besides said (per) fluoropolyether phosphate (component A) the following substancs:
a solvent (component B) selected from the following: linear or branched when possible alcohols from 2 to 3 carbon atoms and methyl ethers thereof; linear or branched glycols from 2 to 6 carbon atoms or linear or branched mono alkyletherified wherein the alkyl group ranges from 1 to 4 carbon atoms; dimethoxymethane, known as methylal, acetone;
water (component C).
Component B) is preferably selected from the following: ethanol, ethylene glycol, isopropanol, propanol, acetone, methoxyethanol, propylene glycol, propan-1,2-diol, dimethoxy methane, methoxy-isopropanol, diethylene glycol, butan-1,4-diol, diethylenglycolmonoethylenether, pentan-1,2-diolo, diethylenglycol monoethylether, dipropylenglycol, dipropylenglycol monomethylether, dipropylenglycol monoethylether; still more preferably: ethanol, pentan-1,2-diol.
In said concentrated compositions the amounts of each component A), B) and C) can range from 0.01% to 70% by weight of the composition, preferably from 20% to 40% by weight, the sum A)+B)+C) being equal to 100% by weight of the concentrated composition.
Still more preferably the concentrated composition contains component A) in a percentage by weight in the range 20% -40%, component B) in the range 30-70% and water in the minimum amount required for obtaining a clear solution, and it is generally comprised between 5 and 30% by weight.
Said concentrated compositions are prepared by a process comprising the following steps:
solubilization or dispersion with partial solubilization of a (per)fluoropolyether phosphate component A) in component B) at room temperature under mild stirring;
addition, under stirring, to the mixture of water component C) initially dropwise, so that component A) does not separate, dispersing the drop so as to restore the intitial appearance of the solution before adding the subsequent aliquots of water, which can be gradually increased until completing the addition.
At the end of the addition of water a clear solution is obtained. In fact the (per)fluoropolyether phosphate as such is not soluble in water but the mixture of the perfluoropolyether phosphate with component B) is on the contrary dilutable with water.
The added water is preferably at a temperature in the range 50xc2x0 C.-60xc2x0 C.
The concentrated solution is then diluted, as indicated in the Examples, with solvents and/or excipients to give the compositions for topical use.
The compositions for topical use contain the preserving system comprising the component A) (per)fluoropolyether phosphate of formula (I) in a percentage by weight in the range 0.01-10%, preferably 0.5-5%, still more preferably 0.5-2%.
Tests carried out by the Applicant have shown that the (per) fluoropolyether phosphate of formula (I) is effective towards gram-positive, gram negative bacteria, yeasts or mono-cellular fungi. It has been found that when the molecular weight of the fluorinated chain Rf is 2,000 the compound is no longer active as a preservative and therefore it cannot be used for the specific use of the present invention.
In the final formulations for topical use the amounts of component B) are reduced, and anyway such as not to result effective in absence of the (per)fluoropolyether phosphate of formula (I).
The concentrations by weight of component B) are generally the same above mentioned for the (per)fluoropolyether phosphate of formula (I).
Preferably in formulations for topical use a 1:1 ratio by weight between the solvent component B) and the (per)fluoropolyropolyether phosphate of formula (I) component A) is used.
Preferably in the compositions for topical use component B) is selected between ethyl alcohol and pentan-1,2-diol, more preferably pentan-1,2-diol.
In the compositions according to the invention preferably the amount of perfluoropolyether phosphate of formula (I) component A) and of solvent component B) is in the range 0.5-2%.
The use that is the object of the present invention is achieved by carrying the (per)fluoropolyether phosphate of formula (I) in the above described concentrated solutions and then diluting with solvents and/or excipients in order to obtain the formulations for topical use containing the above indicated amounts of (per)fluoropolyether phosphate of formula (I).
The following Examples are given for illustrative purposes and they are not limitative of the scope of the invention.